ArticleAmerican journal of human genetics2021
Closing the gap: Systematic integration of multiplexed functional data resolves variants of uncertain significance in BRCA1, TP53, and PTEN.
Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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Who cites it
87 citing papers in PubMed.
- Combining multiplexed functional data to improve variant classification.Genome medicine · 2026Article
- Image-based, pooled phenotyping reveals multidimensional, disease-specific variant effects.Cell · 2026Article
- Domain-Specific Computational, Functional and Structural Methods Enable Interpretation ofCurrent oncology (Toronto, Ont.) · 2026Article
- Novel Partial Loss-of-function STAT3-variant as Cause of Hyper-IgE-Syndrome in a Danish Family with Variable Expressivity.Journal of clinical immunology · 2026Article
- Evidence for G6PD variant classification from multiplexed functional assays.Genome biology · 2026Article
- Rescuing the Function of Missense-Mutated Tumor SuppressorbioRxiv : the preprint server for biology · 2026Article
- Not Forgotten: Patient Experiences with Genetic Variant Reclassifications.medRxiv : the preprint server for health sciences · 2026Article
- Supervised learning of protein variant effects across large-scale mutagenesis datasets.Protein science : a publication of the Protein Society · 2026Article
- Convergence of machine learning and genomics for precision oncology.Nature reviews. Cancer · 2026Review
- Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.Nature reviews. Cardiology · 2026Review
- Evaluation of non-canonical p53 functions in DNA replication and recombination for variant classification.Cell death & disease · 2026Article
- A scalable approach to resolving variants of uncertain significance.bioRxiv : the preprint server for biology · 2026Article
- High-Throughput Methods for Variant Functional Assessment in Cardiac Disease.Circulation. Genomic and precision medicine · 2026Review
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- Multi-omics Differential Inference for Functional Interpretation (MoDIFI): A Statistical Framework to Prioritize Cell Lines for Neurodevelopmental Variants.bioRxiv : the preprint server for biology · 2026Article
- Accurate variant effect estimation in FACS-based deep mutational scanning data with Lilace.Genome biology · 2026Article
- Clinical variant interpretation comparing two saturation genome editing-based functional studies forFrontiers in genetics · 2026Article
- Mapping the Functional Landscape ofmedRxiv : the preprint server for health sciences · 2025Article
- Evidence forbioRxiv : the preprint server for biology · 2025Article
- MaveMD: A functional data resource for genomic medicine.medRxiv : the preprint server for health sciences · 2025Article
27 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors.
Funding
Abstract
Clinical interpretation of missense variants is challenging because the majority identified by genetic testing are rare and their functional effects are unknown. Consequently, most variants are of uncertain significance and cannot be used for clinical diagnosis or management. Although not much can be done to ameliorate variant rarity, multiplexed assays of variant effect (MAVEs), where thousands of single-nucleotide variant effects are simultaneously measured experimentally, provide functional evidence that can help resolve variants of unknown significance (VUSs). However, a rigorous assessment of the clinical value of multiplexed functional data for variant interpretation is lacking. Thus, we systematically combined previously published BRCA1, TP53, and PTEN multiplexed functional data with phenotype and family history data for 324 VUSs identified by a single diagnostic testing laboratory. We curated 49,281 variant functional scores from MAVEs for these three genes and integrated four different TP53 multiplexed functional datasets into a single functional prediction for each variant by using machine learning. We then determined the strength of evidence provided by each multiplexed functional dataset and reevaluated 324 VUSs. Multiplexed functional data were effective in driving variant reclassification when combined with clinical data, eliminating 49% of VUSs for BRCA1, 69% for TP53, and 15% for PTEN. Thus, multiplexed functional data, which are being generated for numerous genes, are poised to have a major impact on clinical variant interpretation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.